Chlorination of carbohydrates and derivatives thereof, such as sugars and their esters, has been known. For example, sucralose, 4,1′,6′-trichloro-4,1′,6′-trideoxygalactosucrose, is an artificial sweetener with a sweetness intensity many times that of sucrose. Sucralose is a sucrose derivative, made by chlorination of a sucrose ester such as sucrose-6-acetate or sucrose-6-benzoate.
Attempts have been made in the industry to improve the reaction conditions, the yield, and/or the reduce the amount of impurities formed during the chlorination reaction. However, the reaction conditions are still harsh, e.g., high reaction temperatures and/or long reaction times are employed. Alternatively, the yields of the trichlorinated ester are low. In some instances, the reported chlorination reaction conditions are not reproducible.
For example, U.S. Pat. No. 4,980,463 to Walkup et al. discloses that when sucrose-6-benzoate is chlorinated with phosgene, only monochlorinated product is formed within the temperature range of 50° C. to about 70° C. The '463 patent discloses that the reaction mixture may be maintained at this temperature for at least 1 hour with little or no di- or higher chlorination occurring.
The '463 patent further discloses that the above monochlorinated reaction mixture must be heated to a temperature range of 75° C. to 100° C. and preferably 80° C. to 85° C. to effect partial dichlorination of the sucrose-6-ester. The '463 patent discloses that at this temperature little or no tri- or higher chlorination occurs and a mixture of primarily monochlorinated sucrose-6-esters plus some dichlorinated sucrose-6-esters results after about 1 hour. The '463 patent further states that maintenance of the reaction mixture at this temperature for longer periods of time results in a higher degree of conversion of monochlorinated sucrose-6-esters to dichlorinated sucrose-6-esters with little or no trichlorination observed by silica gel TLC.
The '463 patent further states that in preferred aspects of the invention, the temperature is increased rapidly, after initially attaining 80° to 85° C., to a temperature sufficient to completely convert monochlorinated sucrose-6-esters to dichlorinated sucrose-6-esters, trichlorinated sucrose-6-esters and little or no tetra- or higher chlorinated sucrose-6-esters. The '463 patent further teaches that the temperatures for this step are usually in the range of about 100° C. to about 130° C. and preferably from about 110° C. to about 125° C. According to the '463 patent, the reaction mixture is held at this temperature for a period sufficient to maximize trichlorination, e.g., from about 1 hour to about 6 hours, and preferably chlorination of sucrose-6-ester at 85° C. produces a mixture of chlorinated sucrose-6-ester products consisting essentially of 6′-chlorosucrose-6-ester, 4,6′-dichlorosucrose-6-ester, and 1′,6′-dichlorosucrose-6-ester. According to the '463 patent, the above mixture must be heated to a temperature not higher than 125° C. for a period of time sufficient to produce a chlorinated product consisting essentially of 1′,4,6′-trichlorosucrose-6-ester.
The '463 patent states that it takes nearly 5 to 6 hours of total reaction time to obtain maximum yields of about 60% of sucralose-benzoate as shown in FIG. 7 of the patent. FIGS. 4 and 5 of the '463 patent, disclosing conversion as a function of reaction time with phosphorous oxychloride, indicate that the sucralose-6-benzoate content reaches a maximum at 4 hours at 115° C., and thereafter drops off, with concomitant increase in higher chlorinated products. In Example 5, the '463 patent discloses that, when phosphorous oxychloride is employed as the chlorinating agent, the yield of sucrose-6-benzoate is only 31.9%.
WO 2008/052076 A2 to Ho et al. discloses a process for the preparation of sucralose by the chlorination of sugar with triphosgene. According to Ho et al., paragraph [0008], the chlorination reaction mixture is heated to 110° C. and refluxed at 110° C. for 3 hours. While Ho et al. contemplates at paragraph [0013] that the chlorination reaction may be carried our under vacuum to avoid the oxidation of the reaction mixture by oxygen in ambient temperature, none of the examples ran the reaction under vacuum.
United States Patent Application Publication No. 2007/0100139 A1 by Fry reportedly discloses methods for chlorinating sucrose-6-esters to produce 1′,4,6′-trichlorosucrose-6-esters including providing a reaction mixture in a temperature-controlled vessel at a temperature less than about 65° C. (abstract). The methods for chlorinating the sucrose-6-ester according to Fry further include subjecting the chloroformiminium chloride salt, tertiary amide, and sucrose-6-ester reaction mixture to an elevated temperature between about 75° C. and 100° C. for a period of time sufficient to produce a chlorinated product mixture of chlorinated sucrose-6-ester products consisting essentially of 1′,4,6′-trichlorogalacto-sucrose-6-ester. In one aspect, Fry recommends maintaining the temperature during chlorination at about 85° C. for about 50 hours to maximize the yield; however, no actual yield value is reported. Fry also teaches that acetic acid may be used to increase the yield of the trichlorinated sucrose ester. However, the present inventors find that some of the assertions made in Fry are not reproducible. The Fry patent application went abandoned for failure to prosecute.
United States Patent Application Publication No. 2007/0207246 A1 by Wang et al. teaches that sugar-6-acetate can be reacted with PCl5 and DMF to obtain sucralose-6-acetate. Wang et al. asserts at paragraph [0040] that trichloroacetonitrile can be used as a catalyst for the chlorination and the temperature of the reaction mixture is raised to 80° C. in 6 hours and maintained there for 3 hours to obtain sucralose-6-acetate. However, the present inventors experienced a reproducibility issue with this method.
In view of the foregoing, there is a desire to have an improved method of chlorinating carbohydrates or derivatives thereof, particularly sucrose esters.